Generalized vitiligo is an autoimmune disorder characterized by acquired white patches of skin and overlying hair due to loss of melanocytes from these areas. Depigmentation is progressive and disfiguring, often resulting in significant psychological trauma. Vitiligo is the most common disorder of pigmentation, with frequency of approximately 0.5% in most populations. Family clustering of cases is not uncommon, in a non-Mendelian pattern suggestive of multifactorial, polygenic inheritance involving both genetic and non-genetic factors. Furthermore, in about half of families vitiligo is associated with autoimmune thyroid disease, pernicious anemia, Addison's disease, lupus, and perhaps inflammatory bowel disease, in both probands and their relatives, indicating that these autoimmune diseases share common etiologic factors, most likely genetic. During the current grant period we surveyed two vitiligo patient groups, the Vitiligo Society (UK) and the National Vitiligo Foundation (USA), ascertaining > 3300 probands, and we subsequently collected and genotyped DNA samples from 94 multiplex Caucasian vitiligo families from this group. By genome-wide genetic linkage analyses, we detected a number of putative linkage signals genome-wide, 3 of which meet genomewide criteria for ' significant' linkage; one of these (AIS1, on 1p) has now been confirmed, showing dominant linkage in larger, autoimmunity-associated vitiligo families. To confirm some of these linkage signals, and to detect others, we now propose to collect and genotype samples from a replicate cohort of 33 larger amd 61 smaller Caucasian families. Confirmed linkage signals will be fine-mapped to determine which can be more finely resolved and linkage signal strength improved. A major aim is the identification of AIS1 by classic positional cloning utilizing large AIS1-linked families. We have already tested a number of genes in the AIS1 interval, and have found potential variants in the FOXD3 promoter that will be now tested for their effect on FOXD3 transcription. Additional patients will be searched for mutations in FOXD3 and in other genes if FOXD3 appears to not be AIS1. A final, related aim to identify one or more additional vitiligo susceptibility genes, depending on linkage results obtained. The long-term significance of this work may be to develop specific approaches to disease therapy and prevention and to apply those modalities to patients at high genetic risk.